Tetrabenazine (I) is a benzoquinoline compound and a vesicular monoamine transporter 2 (VMAT2) inhibitor commonly prescribed for the treatment of Huntington's disease. Deutetrabenazine (II) is a deuterated analog of tetrabenazine (I) which has improved pharmacokinetic properties when compared to the non-deuterated drug. Currently the New Drug Application (NDA) for deutetrabenazine has been accepted by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington disease.
The carbon-hydrogen bonds of tetrabenazine (I) contain a naturally occurring distribution of hydrogen isotopes however increased levels of deuterium incorporation may produce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of tetrabenazine in comparison with tetrabenazine having naturally occurring levels of deuterium.
The U.S. Pat. No. 3,045,021 discloses process for preparation of tetrabenazine (I) and U.S. Pat. No. 8,524,733 discloses deutetrabenazine (II).

The U.S. Pat. No. 3,045,021, provides process for preparation of tetrabenazine (I) which comprises condensation of 6,7-dimethoxy-3,4-dihydroisoquinoline with 3-methylene-5-methyl-2-hexanone (VI) in an alkaline medium.
Another patent GB 999095 described process for preparation of tetrabenazine which involves reaction of 3,4-dihydro-6,7-dimethoxyisoquinoline and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V) in alcohol.
The U.S. Pat. No. 8,524,733, provides process for preparation of deutetrabenazine by reaction of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V) in ethanol. The product is isolated by column chromatography in yield of 35%. The intermediate d6-6,7-Dimethoxy-3,4-dihydroisoquinoline is prepared by series of reaction wherein (E)-4-(2-nitrovinyl) benzene-1,2-diol is reacted with d3-Iodomethane to produce d6-(E)-1,2-Dimethoxy-4-(2-nitrovinyl)benzene which undergoes reduction in presence of lithium aluminum hydride to give 2-(3,4-d6-Dimethoxyphenyl)ethanamine which further reacts with hexamethylenetetramine in presence of acetic acid/trifluoroacetic acid to give the intermediate d6-6,7-Dimethoxy-3,4-dihydroisoquinoline. The process utilizes expensive reagents like d3-Iodomethane, tedious technique of column chromatography resulting in low yields hence is not industrially feasible.
Another patent application US 20150152099 describes process for preparation of deutetrabenazine by reaction of d6-6,7-Dimethoxy-3,4-dihydroisoquinoline and (2-acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (V) in various solvents. The intermediate d6-6,7-Dimethoxy-3,4-dihydroisoquinoline is prepared by series of reaction wherein dopamine hydrochloride reacts with ethyl formate to give N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide which reacts further with d3-Iodomethane to produce deuteriated compound which is cyclized in presence of phosphoryl chloride to give d6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride. The process utilizes expensive reagents like d3-Iodomethane.
The present invention provides novel process for preparation of tetrabenazine (I) and deutetrabenazine (II) which is efficient, industrially viable and cost effective. The present invention provides novel process for preparation of deutetrabenazine (II) that does not involve tedious technique of column chromatography or expensive and non-commercially available d3-Iodomethane.